Department Research Meeting - CAAri PREMIA - Fabrizio Piazza

 

After decades of research and expertise, despite considerable controversies on clinical efficacy, in June 2021 the FDA approved the Aβ-lowering monoclonal antibody (mAbs) aducanumab (Biogen) as the first disease-modifying drug for immunotherapy of Alzheimer’s disease (AD). As per today, two further anti-Aβ mAbs are under FDA accelerated review pathway, with gantenerumab (Roche) that likely will follow soon after data read out in November 2022 and the new generation of mAbs, such as TREM2 agonist mAbs, in the pipeline. 

This means that, irrespective of proofs of clinical efficacy, four mAbs could enter clinical practice in 2023, in an environment where most clinicians have little experience with this type of new drugs and where current MRI biomarkers demonstrated to have several important limitations in the prediction, monitoring, and treatment decisions. In fact, these drugs demonstrated a dose and time-dependent associated incidence of amyloid-related imaging abnormalities (ARIAs) side effects in up to 50% of the treated patients. 

Notably, the EMA has denied approval of aducanumab in Europe, due to outweighted risk-to-benefit consequences of treatment and pending the availability of future convincing monitoring plans for ARIA management.

In this framework, our group pioneered in demonstrating that therapy-induced ARIA are the iatrogenic manifestation of cerebral-amyloid angiopathy (CAA)-related inflammation (CAA-ri), an autoimmune encephalopathy characterized by raised anti-Aβ autoAbs (aAbs) in the cerebrospinal fluid (CSF). Indeed, the longitudinal monitoring of CSF aAbs levels in CAA-ri demonstrated a regional and temporal association with ARIA-edema (ARIA-E) (often preceding the occurrence of ARIA-Hemorrhage), focal areas of neuroinflammation, reduced Aβ-PET uptake, and ATN biomarkers profile change suggestive of impaired intramural periarterial clearance pathways, particularly in patients with coexisting AD and CAA comorbid pathology and carrying of the ApoE4 allele. 

In this framework, we will discuss current emerging evidence indicating the CSF testing for aAbs as a strategic companion biomarker for treatment and monitoring decisions in real clinical practice and in Aβ-lowering immunotherapy trials, including patients' selection, risk stratification, and treatment response.

 

 

He is leading translational research aimed at improving patient care by accelerating the development and delivery of personalized healthcare, including personalized therapies and diagnostics applied to neurodegenerative, neuroimmunological and cerebrovascular disorders. He served as an Academic Scientific Consultant and Advisor for Roche, Genentech, Alector, Prothena, Biogen.

He is the founding Member and Coordinator of the inflammatory Cerebral Amyloid Angiopathy and Alzheimer’s disease βiomarkers International Network (iCAβ), a World-Wide Consortium involving 35 leading Centers of Excellence on AD and CAA from 12 different Countries.

The validation of biomarkers and the definition of clinico-therapeutic recommendations for CAA and CAA-ri is the main goal of the iCAB International Network, the largest worldwide effort aimed at deciphering the pathogenic mechanism of CAA-ri and ARIA in a translational and cooperatively-open design between Academia and Pharma industries.

 

WebSite:  https://sites.google.com/site/icabinternationalnetwork